Do Adverse Childhood Experiences Make Us More Utilitarian in Moral Dilemmas?

Purpose: Adverse childhood experiences (ACEs) have been associated with various aspects of morality, but their precise impact on moral decision-making remains unclear. This study aims to explore how ACEs influence moral decision-making in sacrificial dilemmas. Methods: Study 1 employed traditional dilemma analysis to quantify utilitarian responses and compare them among groups with no, low, and high ACEs. Study 2 utilized the CNI model to quantify three determinants of moral decision-making: sensitivity to consequences (C parameter), sensitivity to norms (N parameter), and general action tendencies (I parameter). Differences in these parameters among groups with no, low, and high ACEs were investigated. Results: Both Study 1 and Study 2 revealed that the high-ACE and low-ACE groups showed significantly higher utilitarian responses compared to the no-ACE group. However, no notable differences emerged between the high-ACE and low-ACE groups. Study 2 found that the N parameter was significantly lower in the high-ACE group compared to the low and no-ACE groups. Similarly, the low-ACE group exhibited significantly lower scores in the N parameter compared to the no-ACE group. Additionally, no significant differences were observed in the C and I parameters among groups with no, low, and high ACEs. Conclusion: These findings suggest that individuals with a high number of ACEs tend to exhibit more utilitarian responses, attributed to decreased affective response to the violation of moral rules, rather than increased deliberative cost-benefit reasoning or a general preference for action. Such insights deepen our understanding of the precise aspects of moral decision-making influenced by ACEs.

pH-Activated Scallop-Type Nanoenzymes for Oxidative Stress Amplification and Photothermal Enhancement of Antibacterial and Antibiofilm Effect.

Ferric phosphate (FePOs) nanoenzymes can express peroxidase (POD) activity under the dual stimulation of an acidic environment and high H2O2 concentrations. In living organisms, this generates reactive oxygen species (ROS) in sites of lesion infection, and thus FePOs nanoenzymes can act as antimicrobial agents. Here, CeO2 and ZnO2 were immobilized in a scallop-type FePOs nanoenzyme material loaded with a photosensitizer, indocyanine green, to synthesize a multifunctional cascade nanoparticle system (FePOs-CeO2-ZnO2-ICG, FCZI NPs). H2O2 concentrations could be adjusted through the ZnO2 self-activation response to the slightly acidic environment in biofilms, further promoting the release of ROS from the POD-like reaction of FePOs, achieving amplification of oxidative stress, DNA and cell membrane damage, and exploiting the photodynamic/photothermal effects of indocyanine green to enhance the antibiofilm effects. CeO2 can remove redundant ROS by switching from Ce4+ to Ce3+ valence, enhancing its ability to fight chronic inflammation and oxidative stress and thus promoting the regeneration of tissues around infection. By maintaining the redox balance of normal cells, increasing ROS at the infection site, eliminating redundant ROS, and protecting normal tissues from damage, the synthesized system maximizes the elimination of biofilms and treatment at the infection site. Therefore, this work may pave the way for the application of biocompatible nanoenzymes.

PTT/ PDT-induced microbial apoptosis and wound healing depend on immune activation and macrophage phenotype transformation.

Antibiotics show unsuccessful application in biofilm destruction, which induce chronic infections and emergence of antibiotic resistant bacteria. Photodynamic therapy (PDT) and photothermal therapy (PTT), as widely accepted antimicrobial tools of phototherapy, could effectively activate the immune system and promote the proliferation of wound tissue, thus becoming the most promising therapeutic strategy to replace antibiotics and avoid drug-resistant strains. However, there is no consensus on whether antibacterial and wound healing achieved by PDT/PTT depend not only on the cytotoxic effect of the treatment itself, but also on the activation of host immune system. In this study, CaSiO3-ClO2@PDA-ICG nanoparticles (CCPI NPs) were designed as PDT/PTT antimicrobial model material. With the comparison of healing effect between wide-type mice and severely immunodeficient (C-NKG) mice, the dependence of PDT/PTT-induced microbial apoptosis and wound healing on immune activation and macrophage phenotype transformation was explored and verified. Furthermore, the induced phenotypic transformation of macrophages during PDT/PTT treatment was demonstrated to play crucial role in the improvement of epithelial-mesenchymal transformation (EMT). In summary, this study represents great significance for further identifying the role of immune system activation in antibacterial phototherapy and developing new treatment strategies for biofilm-infected wound healing. STATEMENT OF SIGNIFICANCE: A PDT/PTT combination therapy model nanoparticle was established for biofilm-infected wounds. Both microbial apoptosis and wound healing achieved by PDT/PTT combination therapy were highly dependent on the activated immune system, especially the M2 macrophage phenotype. PDT/PTT could promote the polarization of monocytes to the phenotype of M2 macrophages, which promotes EMT behavior of the tissue at the edge of the wound through the secretion of TGF-ß1, thus accelerating wound healing.

Three-dimension chitosan hydrogel loading melanin composite nanoparticles for wound healing by anti-bacteria, immune activation and macrophage autophagy promotion.

Application of Combined photodynamic therapy (PDT) and photothermal therapy (PTT) has become one of the most promising strategy to replace antibiotics and avoid the epidemic of drug-resistant strains during wound healing. However, high amount of reactive oxygen species (ROS) and high temperature cause severe stress response to normal tissues, leading to potential risks of wound healing. Herein, a three-dimension chitosan hydrogel melanin-glycine-C60 nanoparticles (MGC NPs) were prepared to realized effective anti-bacterial activity, immune activation and macrophage autophagy promotion in three-dimensional wound space without triggering stress response. MGC NP is a composite polymer material composed of natural melanin polymer, oligopeptide and carbon-based material, which showed excellent biological safety. By regulating the peptide length between melanin and C60 and nanoparticle content, a high ROS/heat environment at the upper wound site and a low ROS/heat environment at the lower region adjacent to the wound tissue were established to obtain a three-dimension hydrogel with precise PDT and PTT efficiency in different regions. Highly effective PDT/PTT was used to kill microorganisms in upper region, thus providing a barrier to reduce microbial infection. Mild PDT/PTT in lower region promoted the polarization of M1 macrophage to M2 macrophage and activated autophagy of M2 macrophages, regulating the immune microenvironment and promoting wound repair. In conclusion, the novel three-dimensional PDT/PTT therapy based on natural macromolecules proposed in this study accelerates wound healing through dual pathways on the premise of avoiding wound stress response, which is of great significance for the development of clinical strategies for phototherapy.

Hui Medicine Moxibustion Promotes the Absorption of Lumbar Disc Herniation and the Recovery of Motor Function in Rats through Fas/FasL Signaling Pathway.

Objectives: To study the resorption of the herniated lumbar disc (RHLD) and its mechanism in the SD rats of lumbar intervertebral disc herniation treated with Hui medicine moxibustion (HMM). Methods: Forty SD rats were randomly divided into four groups, normal group, lumbar disc herniation (LDH) group, HMM group, and antagonist (HMM+Met12) group, with 10 rats in each group. The rat model of LDH was prepared with the method of lumbar epidural emplacement of the caudal intervertebral disc. In the HMM group and HMM+Met12 groups, 4 weeks after modeling, HMM therapy was performed in the lumbar spine for 3 months with 1 time per day and 20 min each time, the samples were collected 8 weeks after the treatment. The histological degeneration was observed through HE staining, and the neovascularization of intervertebral disc tissues was detected by the expression of CD34 and vascular endothelial growth factor (VEGF). The apoptosis of nucleus pulpous cells was detected by TUNEL assay, and the activity of caspase-3, -8, and -9 and extracellular matrix enzymes was detected by western blotting. Results: HMM treatment significantly improved the behavioral ability of rats with LDH surgery. The morphological structure was obviously destroyed in the LDH group, but disc structure was significantly repaired in the HMM group, and mild structure alterations were observed in the HMM+Met12 group. Higher levels of CD34 and VEGF were detected in the HMM group indicating that neovascularization is formed. The expression level of FasL was significantly increased in the HMM group. The protein expression levels of cleaved-caspase-3, cleaved-caspase-8, and cleaved-caspase-9 in nucleus pulposus (NP) tissues were also elevated when treated with HMM, and the TUNEL staining showed the same results. The protein expression levels of matrix metalloproteinases- (MMP-) 1, MMP-2, MMP-3, MMP-13, and ADAMTS-4 were markedly promoted in the HMM group. Met12, a small peptide antagonist of FasL, significantly reduced the effects of HMM. Conclusion: HMM can promote the formation of neovascularization of lumbar intervertebral disc, support the apoptosis of NP cells through Fas/FasL signaling, and regulate the degradation of extracellular matrix enzyme, which then accelerates the absorption of lumbar intervertebral disc herniation and the recovery of motor function in rats.

pH-Regulating Nanoplatform for the "Double Channel Chase " of Tumor Cells by the Synergistic Cascade between Chlorine Treatment and Methionine-Depletion Starvation Therapy.

During rapid proliferation and metabolism, tumor cells show a high dependence on methionine. The deficiency of methionine exhibits significant inhibition on tumor growth, which provides a potential therapeutic target in tumor therapy. Herein, ClO2-loaded nanoparticles (fluvastatin sodium&metformin&bupivacaine&ClO2@CaSiO3@MnO2-arginine-glycine-aspatic acid (RGD) (MFBC@CMR) NPs) were prepared for synergistic chlorine treatment and methionine-depletion starvation therapy. After outer layer MnO2 was degraded in the high glutathione (GSH) tumor microenvironment (TME), MFBC@CMR NPs released metformin (Me) to target the mitochondria, thus interfering with the tricarboxylic acid (TCA) cycle and promoting the production of lactate. In addition, released fluvastatin sodium (Flu) by the NPs acted on monocarboxylic acid transporter 4 (MCT4) in the cell membrane to inhibit lactate leakage and induce a decrease of intracellular pH, further prompting the NPs to release chlorine dioxide (ClO2), which then oxidized methionine, inhibited tumor growth, and produced large numbers of Cl- in the cytoplasm. Cl- could enter mitochondria through the voltage-dependent anion channel (VDAC) channel, which was opened by bupivacaine (Bup). The disruption of Cl- homeostasis promotes mitochondrial damage and membrane potential decline, leading to the release of cytochrome C (Cyt-C) and apoptosis inducing factor (AIF) and further inducing cell apoptosis. To sum up, the pH-regulating and ClO2-loaded MFBC@CMR nanoplatform can achieve cascade chlorine treatment and methionine-depletion starvation therapy toward tumor cells, which is of great significance for improving the clinical tumor treatment effect.

Relative pose estimation of uncooperative spacecraft using 2D-3D line correspondences.

The relative pose estimation of uncooperative spacecraft is an essential technology in space missions. However, lacking the prior knowledge of uncooperative targets brings great challenges to accurately measure their pose, which hinders their application in space. To overcome these problems, an accurate and robust pose estimation approach for uncooperative spacecraft is proposed based on a time-of-flight camera coupled with a gray-scale camera. We reconstruct the target model using our hierarchical registration strategy by the ToF camera and extract 2D lines from image sequences captured by the gray-scale camera. We attempt to establish 2D-3D line correspondences for pose estimation, which effectively associates the 2D image information with the reconstructed 3D model. Experimental results manifest that, when dealing with a completely unknown model, our method computes its relative position and attitude with significantly high accuracy.

Jinzhi protects lipopolysaccharide-treated mice against mortality by repairing intestinal mucosal barrier damage and intestinal microecology.

OBJECTIVE: Intestinal mucosal barrier damage is an important mechanism for the development of sepsis and multiple organ dysfunction syndrome. At present, there are no satisfactory and effective methods for the protection of the intestinal mucosal barrier. Jinzhi, the first fecal microbiota transplantation worldwide, is often used to treat critically ill patients; however, the specific mechanism involved in this process remains unclear. The aim of this study was to investigate the therapeutic effect and mechanism of Jinzhi intervention on mice with sepsis induced through treatment with lipopolysaccharide (LPS). METHODS: Mice were intraperitoneally injected with LPS to simulate intestinal mucosal barrier function damage in sepsis; intervention was performed through the oral administration of Jinzhi. The effect of Jinzhi on LPS-induced sepsis was analyzed by comparing the vital signs and survival rate of mice under different treatments. Pathological staining and enzyme-linked immunosorbent assay were used to identify the effects of LPS or treatment with Jinzhi on the intestinal mucosal barrier in mice. The effect of LPS or treatment with Jinzhi on the intestinal flora was analyzed via 16S rRNA gene sequencing of ileal contents. RESULTS: Immunohistochemistry and enzyme-linked immunosorbent assay showed that treatment with LPS increased levels of inflammatory factors (interleukin-1α, interleukin-6, tumor necrosis factor-α), caspase-3, and caspase-8 in the serum and ileum, and destroyed the tight junction between epithelial cells. Intervention with Jinzhi reduced levels of serum LPS and tumor necrosis factor-α, and repaired the tight junction between epithelial cells. Furthermore, 16S rRNA gene sequencing analysis showed that treatment with Jinzhi improved the diversity and physiological function of the intestinal flora. CONCLUSIONS: These results suggest that Jinzhi may be a promising option for the treatment of sepsis caused by LPS, and emphasize that Jinzhi exerts a recovery effect on the imbalance of intestinal flora.

Interaction of tryptophan hydroxylase 2 gene and life events in susceptibility to major depression in a Chinese Han population.

BACKGROUND: Major depression (MD) results from a complex synergy between genetic and environmental factors. The aim of this study is to analyze the interaction of tryptophan hydroxylase 2 gene (TPH2) variation and negative life events in the pathogenesis of MD. Three TPH2 polymorphisms, -703G/T (rs4570625), -473T/A (rs11178997), and 1463G/A (rs120074175), were selected based on previous findings of associations with MD. METHODS: In this study, 289 patients with MD and 289 age- and sex-matched control subjects were genotyped. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). Gene-environment interactions (G×E) were assessed using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS: Differences in rs11178997 and rs120074175 allele frequencies and genotype distributions were observed between MD patients and controls. Significant G×E interactions between negative life events and allelic variation of rs4570625, rs11178997, and rs120074175 were also observed. Individuals carrying the T(-) genotype of rs4570625 (GG), T(-) genotype of rs11178997 (AA), or A(-) genotype of rs120074175 (GG) were susceptible to MD only when exposed to high-negative life events. However, individuals with the T(+) genotypes of rs11178997 (TA, TT) and A(+) genotypes of rs120074175 (AG, AA) were susceptible to MD when exposed to low-negative life events. LIMITATION: Assessment of negative life events was influenced by subjective interpretation. CONCLUSIONS: Interactions between multiple TPH2 gene alleles and negative life events were revealed by GMDR analysis. Chinese Han individuals with at least one rs11178997 T allele or rs120074175 A allele are susceptible to MD even in the relative absence of high-negative life events.

Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction.

Mitochondria are the most important sensor for apoptosis. Extracellular adenosine is well reported to induce apoptosis of tumor cells. Here we found that extracellular adenosine suppresses the cell growth by induction of apoptosis in BEL-7404 liver cancer cells, and identified a novel mechanism that extracellular adenosine triggers apoptosis by increasing Reactive Oxygen Species (ROS) production and mitochondrial membrane dysfunction in the cells. We observed that adenosine increases ROS production, activates c-Caspase-8 and -9 and Caspase effectors, c-Caspase-3 and c-PARP, induces accumulation of apoptosis regulator Bak, decreases Bcl-xL and Mcl-1, and causes the mitochondrial membrane dysfunction and the release of DIABLO, Cytochrome C, and AIF from mitochondria to cytoplasm in the cells; ROS inhibitor, NAC significantly reduces adenosine-induced ROS production; it also shows the same degree of blocking adenosine-induced loss of mitochondrial membrane potential (MMP) and apoptosis. Our study first observed that adenosine increases ROS production in tumor cells and identified the positive feedback loop for ROS-mediated mitochondrial membrane dysfunction which amplifies the death signals in the cells. Our findings indicated ROS production and mitochondrial dysfunction play a key role in adenosine-induced apoptosis of 7404 cells.

Induction of senescence by adenosine suppressing the growth of lung cancer cells.

Extracellular adenosine is well reported to suppress tumor growth by induction of apoptosis. However, in this study we found that adenosine treatment results in cellular senescence in A549 lung cancer cells both in vitro and in vivo; adenosine induces cell cycle arrest and senescence in a p53/p21 dependent manner; adenosine elevates the level of phosphor-γH2AX, pCHK2 and pBRCA1, the markers for prolonged DNA damage response which are likely responsible for initiating the cellular senescence. Our study first demonstrates that adenosine suppresses growth of cancer cells by inducing senescence and provides additional evidence that adenosine could act as an effective anticancer agent for targeted cancer therapy.

Designer lipid-like peptides: a class of detergents for studying functional olfactory receptors using commercial cell-free systems.

A crucial bottleneck in membrane protein studies, particularly G-protein coupled receptors, is the notorious difficulty of finding an optimal detergent that can solubilize them and maintain their stability and function. Here we report rapid production of 12 unique mammalian olfactory receptors using short designer lipid-like peptides as detergents. The peptides were able to solubilize and stabilize each receptor. Circular dichroism showed that the purified olfactory receptors had alpha-helical secondary structures. Microscale thermophoresis suggested that the receptors were functional and bound their odorants. Blot intensity measurements indicated that milligram quantities of each olfactory receptor could be produced with at least one peptide detergent. The peptide detergents' capability was comparable to that of the detergent Brij-35. The ability of 10 peptide detergents to functionally solubilize 12 olfactory receptors demonstrates their usefulness as a new class of detergents for olfactory receptors, and possibly other G-protein coupled receptors and membrane proteins.

A robust and rapid method of producing soluble, stable, and functional G-protein coupled receptors.

Membrane proteins, particularly G-protein coupled receptors (GPCRs), are notoriously difficult to express. Using commercial E. coli cell-free systems with the detergent Brij-35, we could rapidly produce milligram quantities of 13 unique GPCRs. Immunoaffinity purification yielded receptors at >90% purity. Secondary structure analysis using circular dichroism indicated that the purified receptors were properly folded. Microscale thermophoresis, a novel label-free and surface-free detection technique that uses thermal gradients, showed that these receptors bound their ligands. The secondary structure and ligand-binding results from cell-free produced proteins were comparable to those expressed and purified from HEK293 cells. Our study demonstrates that cell-free protein production using commercially available kits and optimal detergents is a robust technology that can be used to produce sufficient GPCRs for biochemical, structural, and functional analyses. This robust and simple method may further stimulate others to study the structure and function of membrane proteins.

SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.

Obtaining functional data with newly identified rare variants increases certainty that the variant identified is relevant for dilated cardiomyopathy (DCM) causation. Two novel SCN5A rare variants, R222Q and I1835T, segregated with DCM in two families with affected individuals homozygous or heterozygous for the common SCN5A polymorphism H558R. cDNAs with each rare variant were constructed in the common Q1077del or Q1077 splice variant backgrounds with and without the H558R polymorphism and expressed in HEK293 cells. Sodium current (I(Na) ) was studied for each using whole-cell voltage clamp. In the Q1077del background I(Na) densities of R222Q and I1835T were not different from wild type, but the combined variants of R222Q/H558R, I1835T/H558R caused approximately 35% and approximately 30% reduction, respectively, and each showed slower recovery from inactivation. In the Q1077del background R222Q and R222Q/H558R also exhibited a significant negative shift in both activation and inactivation while I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak I(Na) densities, decay, or recovery from inactivation for R222Q/H558R and I1835T/H558R. We conclude that the biophysical findings, dependent upon common SCN5A variants, provide further evidence that these novel SCN5A rare variants are relevant for DCM.